The overall objectives of this proposal are the development and characterization of new genetic stocks of immunodeficient mice that will support the growth of human hematolymphoid cells, thus facilitating infection with human immunodeficiency virus (HIV). The development of a small animal model for AIDS research has been advanced by the recent findings that strain C.B-17 mice homozygous for the mutation severe combined immunodeficiency (scid) support the growth of human fetal lymphoid tissue and the engraftment with adult hum peripheral blood lymphocytes (PBL). Such fetal as well as adult human hematolymphoid cells are permissive for infection with HIV. Although the use of scid/scid mice as hosts for HIV-infected human hematolymphoid cells offers great promise as a small animal model for AIDS research, the engraftment of these immunodeficient mice with such cells is limited by the activity of host murine natural killer (NK) cells and by the extreme radiosensitivity of these mice. The major emphasis of our genetic manipulations is to construct stocks of scid/scid mice that have decreased levels of NK cell activity. Depletion of NK cells will be accomplished by backcrossing scid onto strain backgrounds (SJL/J and NOD/Lt) with low endogenous NK cell activity and onto a strain background (C57BL/6J) that will enable in vivo depletion of NK cells with the anti-NK 1.1 monoclonal antibody. An additional series of crosses will produce mice simultaneously homozygous for scid/scid and for the autosomal recessive mutation beige (bg); homozygosity for the bg allele causes severe depression of NK cell activity. Finally, a stock of hematopoietic stem cell-defective scid/scid W41/W41 mice will be constructed to facilitate repopulation with human bone marrow without the need to irradiate the host animals. Construction of this stem cell-defective stock takes advantage of a novel mutation (W41) at the dominant spotting (W) locus. These NK cell-depleted and hematopoietic stem cell-defective stocks of scid/scid mice will be characterized for histopathological, hematological and immunological abnormalities. The ability of these new stocks of scid/scid mice to support reconstitution with human hematolymphoid cells and the permissiveness of these engrafted human cells to infection with HIV will be evaluated.